Breast cancer is the most commonly diagnosed cancer in women in both United States and worldwide. Breast cancer rates are the highest in industrialized countries. In the United States, the incidence of breast cancer has more than doubled in the past 30 years. In 1964, the lifetime risk was 1 in 20. Today it's 1 in 8. Approximately 185,700 new cases are diagnosed in the U.S. annually, and breast cancer is responsible for about 44,560 deaths in the U.S. per year. An estimated 3 million women in the U.S. today are living with breast cancer of which 2 million have been diagnosed with the disease and 1 million have the disease but do not yet know it. Worldwide, it is estimated that 1.2 million new diagnoses and 500,000 deaths from breast cancer will occur this year.
While predominantly observed in women, 1,400 cases of breast cancer are diagnosed annually in men, and 260 men die of breast cancer per year. When breast cancer does occur in men, it is usually not recognized until late, and thus, the results of treatment are poor. In women, carcinoma of the breast is rarely seen before the age of 30 and the incidence rises rapidly after menopause.
Breast cancer often first manifests itself as a painless lump, detectable by self-examination and clinical breast exams including mammograms. Commonly, growth initiates in the lining of the ducts or in the lobules of the breast.
No universally successful method for the prevention or treatment of breast cancer is currently available. Management of the disease currently relies on a combination of early diagnosis (through routine breast screening procedures) and aggressive treatment, which may include one or more of surgery, radiotherapy, chemotherapy and hormone therapy. Current surgical treatments include mastectomy (removal of the entire breast) or lumpectomy (removal of the tumor and surrounding tissue) for localized tumors. Localized disease can be effectively treated by surgery, if all of the cancer can be removed. Surgical treatment is often followed by chemotherapy, radiotherapy, or hormone-blocking therapy, especially if the disease has metastatized. Breast cancer cells can metastasize to the lymph nodes, skin, lungs, liver, brain, or bones. Metastasis may occur early or late in the disease progression, although typically metastasis occurs once the cancerous growth reaches a size of about 20 mm. Currently, there are no therapies that are effective for long term treatment of breast cancer that has metastasized to lymph nodes or distal sites.
It has been reported that certain vitamin D compounds and analogues are potent inhibitors of malignant cell proliferation and are inducers/stimulators of cell differentiation. For example, U.S. Pat. No. 4,391,802 issued to Suda et al. discloses that 1α-hydroxyvitamin D compounds, specifically 1α,25-dihydroxyvitamin D3 and 1α-hydroxyvitamin D3, possess potent antileukemic activity by virtue of inducing the differentiation of malignant cells (specifically leukemia cells) to nonmalignant macrophages (monocytes), and are useful in the treatment of leukemia. Antiproliferative and differentiating actions of 1α,25-dihydroxyvitamin D3 and other vitamin D3 analogues have also been reported with respect to cancer cell lines. More recently, an association between vitamin D receptor gene polymorphism and cancer risk has been reported, suggesting that vitamin D receptors may have a role in the development, and possible treatment, of cancer.
Previous studies of vitamin D compounds and cancer treatment have focused exclusively on vitamin D3 compounds. Even though these compounds may indeed be highly effective in promoting differentiation in malignant cells in culture, their practical use in differentiation therapy as anticancer agents is severely limited because of their equally high potency as agents affecting calcium metabolism. At the levels required in vivo for effective use as, for example, antileukemic agents, these same compounds can induce markedly elevated and potentially dangerous blood calcium levels by virtue of their inherent calcemic activity. That is, the clinical use of 1α,25-dihydroxyvitamin D3 and other vitamin D3 analogues as anticancer agents is severely limited by the risk of hypercalcemia. This indicates a need for compounds with greater specific activity and selectivity of action, i.e., vitamin D compounds with antiproliferative and differentiating effects but which have less calcemic activity. It also indicates a need for co-administration agents which can be combined with vitamin D3 agents, allowing for smaller doses of vitamin D3 compounds to be used while achieving the same or greater beneficial effect.